Introduction: Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disorder caused by mutations in the DMD gene, which encodes dystrophin, a crucial protein found at the muscle cell membrane. NS-089/NCNP-02 (brogidirsen) is designed for dual-targeting exon 44 skipping and was developed by the National Center of Neurology and Psychiatry (NCNP) in collaboration with Nippon Shinyaku Co., Ltd. Based on the preclinical outcome of highly effective exon skipping and restoration of dystrophin in cells derived from DMD patients amenable to exon 44 skipping therapy, first-in-human/Phase 1/2 open-label investigator-initiated clinical study (NCNP/DMT02, NCT04129294) and the subsequent Phase 2 open-label extension study (NS089/NCNP02-P2OE, NCT05135663) were conducted in these patients.
Methods: Six participants with DMD in the Phase 2 extension study had previously completed the Phase 1/2 study. Participants continue to receive brogidirsen at doses of 40 mg/kg (n=3) or 80 mg/kg (n=3). The safety and efficacy of brogidirsen after 4.5 years of weekly administration are evaluated in these six participants.
Results: No serious or severe adverse events—including anaphylaxis—or treatment discontinuations were reported during the 4.5-year period of continued weekly brogidirsen administration. In addition, there were improvements or maintained motor function among participants from the initiation of weekly administration in assessments such as North Star Ambulatory Assessment (NSAA). Even participants who had transitioned to wheelchair use due to disease progression maintained their total scores in Performance of Upper Limb (PUL 2.0). Serum creatine kinase levels tended to decrease during the 24 weeks of administration in Phase 1/2 Study and remained stable in Phase 2 extension study.
Conclusion: Brogidirsen has an acceptable safety profile and may modify DMD progression according to the ongoing Phase 2 extension study results. A second Phase 2 study, DISCOVER, (NS-089/NCNP-02-201, NCT05996003) sponsored by NS Pharma, Inc. is ongoing to further evaluate the safety and efficacy of brogidirsen.